The Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is highly expressed in multiple cancers and inflammatory disorders where it stimulates secretion of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. EMMPRIN is amongst a subset of unique proteins that exist as a transmembrane protein but is released by cells in multiple uncharacterized forms. These extracellular forms have already been linked to at least half a dozen cancers and have been shown to contribute to a positive feedback loop during cancer progression. Thus, identifying the specific extracellular forms of EMMPRIN, characterizing how each of these forms contributes to disease progression, and identifying their cellular targets would significantly contribute to our understanding of cancer and inflammation. We have taken an integrative approach to fully characterize EMMPRIN and its role in disease progression by combining biological, biochemical, and atomic resolution studies. Our biological studies have already identified several extracellular forms of EMMPRIN in human blood and released by cancer cells that and the specific MMPs/cytokines secreted by these forms will be fully characterized here (Aim 1). To this end, we have developed recombinant expression systems that produce all the necessary proteins. We will then identify the cellular targets of these EMMPRIN forms by utilizing our recombinant proteins and characterize their interactions (Aim 2). Finally, we have begun solving the X-ray crystal structure and characterizing the solution behavior of a retinal-specific EMMPRIN isoform that contributes to retinoblastoma and here we will characterize this isoform both biophysically and biologically (Aim 3). Since EMMPRIN over-expression results in the deregulation of entire protein families integrally involved in the progression of multiple diseases, our combined biological and biophysical approach will fully characterize extracellular EMMPRIN at the biological and molecular levels, respectively.